Background and Purpose: Humans have been fighting vitiligo for centuries
but still being inferior due to the lack of efficiency drugs and
therapies. While some research has implied the therapeutic potential of
Wnt/β-catenin signalling on curing vitiligo but correlation mechanism is
not clear and no Wnt-specific anti-vitiligo drug has been reported.
Here, We identified how vitiligo could be treated by regulating Wnt and
two lead compounds of new anti-vitiligo drugs have been found.
Experimental Approach: Wnt agonists were rational synthesized and then
be evaluated their effects on vitiligo in B16 cells and C57B/L mouse.
Furthermore, Co-IP and Site-directed mutagenesis were employed to
indicate the mechanism and the target of the compounds. Key Results:
HCJA121 and HCJA404 could significantly promote the synthesis of
melanin, restore the pigmented function of skin, and improve the
symptoms of vitiligo. Mechanism studies indicated that HCJA121 and
HCJA404 target the DAX domain of Axin by binding to LYS781 and LEU784
then potentiate the Axin-LRP6 association and eventually promoted
melanogenesis. Conclusions and Implications: These findings imply an
alternative regulatory mechanism of melanogenesis and the Axin protein
could be a new target for anti-vitiligo agents which reveal a
therapeutic strategy for vitiligo. Besides, HCJA121 and HCJA404 may
represent potential compounds for vitiligo treatment.
Merging crystallography, site-directed mutagenesis and molecular modelling to unravel the regulatory mechanism of photosynthetic GAPDH